The phosphoinositide 3-kinase (PI3K)/3-phospho-inositide-dependent kinase 1 (PDK1)/protein kinase B (Akt) signaling pathway plays vital roles in the transduction of extracellular cues that control multiple aspects of biological processes, including cell growth, survival, protein translation, metabolism, and angiogenesis. Dysregulation of this pathway is also thought to be correlated with the pathogenesis of many human diseases including cancer, as well as metabolic, cardiovascular, and neurological disorders (Chang et al., 2010; Dimmeler and Zeiher, 2000a; Portt et al., 2011; Raff, 1992; Thompson, 1995; Toker and Newton, 2000). Numerous studies illustrate that abnormal activation of the Akt pathway is one of the principal causative factors for the onset and progression of human cancers (Vivanco and Sawyers, 2002). Oncogenic mutations of Akt pathway regulators such as PI3K, PTEN, and PDK1 were commonly detected in many types of cancers in the breast, endometrium, prostate, liver, lung, brain and skin (Raimondi and Falasca, 2011; Sheppard et al., 2012). The Akt pathway is involved in tumor angiogenesis and the epithelial to mesenchymal transition process, which play essential roles in cancer metastasis and the generation of cancer stem cells (Chang et al., 2013; Sheppard et al., 2012). Moreover, Akt serves as a crucial downstream mediator of angiogenic ligands in endothelial cells (ECs) including VEGF, and coordinates diverse aspects of vascular functionality including EC survival, proliferation, migration, permeability, vascular tone, and angiogenesis (Dimmeler and Zeiher, 2000b; Liu et al., 2000; Vicent et al., 2003). Thus, the regulators of the PI3K/Akt pathway have become attractive targets for cancer prevention and chemotherapy. Currently, diverse classes of PI3K/Akt pathway inhibitors are being assessed for cancer-related clinical trials.
In general, the PI3K/Akt pathway is triggered by multiple stimuli such as growth factors, cytokines, cell to cell junctions, and the ECM (Bischoff, 1995; Dimmeler and Zeiher, 2000b; Lamalice et al., 2007; Strømblad and Cheresh, 1996). Once PI3K signaling is activated by a stimulus, phosphatidylinositol-(3,4,5)-triphosphate (PIP3), a product of PI3K, recruits the pleckstrin homology (PH) domain of PDK1 to the plasma membrane, which results in activation of membrane associated Akt at Thr308 (Datta et al., 1999; Lim et al., 2003; Mora et al., 2004; Pearce et al., 2010; Primo et al., 2007). Alternatively, when PIP3-induced Akt conformation changes occur prior to Thr308 phosphorylation by PDK1, conformational changes that permit Ser473 phosphorylation by mammalian target of rapamycin complex 2 can likewise occur. However, Akt phosphorylation at Ser473 also occurred by mammalian target of rapamycin complex 2 (mTOR2) independently of PIP3 (Huang et al., 2011; King et al., 1997). In addition, PIP3 binding activates PDK1 by promoting Ser241 autophosphorylation (Gao and Harris, 2006). The mutation of PDK1 at the Ser241 residue causes a significant reduction in PDK1 activity towards Akt (Casamayor et al., 1999). However, the additional mechanisms of PDK1 localization to the plasma membrane following Akt activation require further clarification.
Throughout the entire specification, many papers and patent documents are referenced and their citations are represented. The disclosure of cited papers and patent documents are entirely incorporated by reference into the present specification, and the level of the technical field within which the present invention falls, and details of the present invention are explained more clearly.